fig_num,image_path,image_caption,golden_corpus,positive_corpus
Figure 4.1,neuroscience/images/Figure 4.1.jpg,Figure 4.1: Metabolism of phenylalanine requires BH4 and also produces tyrosine. Deficiencies in cofactor or phenylalanine hydroxylase can result in phenylketonuria.,"Phenylalanine (Phe) is an essential amino acid, and hydroxylation of Phe by phenylalanine hydroxylase (PAH) generates tyrosine (figure 4.1). This conversion requires BH4, and deficiencies in either the cofactor or the enzyme PAH can result in phenylketonuria. Additionally, the inability to synthesize tyrosine will make this a conditionally essential amino acid and potentially negatively impact the synthesis of downstream compounds illustrated in figure 4.2.","{'78effb87-80dd-42a6-940d-801ba33f16f9': 'Phenylalanine (Phe) is an essential amino acid, and hydroxylation of Phe by phenylalanine hydroxylase (PAH) generates tyrosine (figure 4.1). This conversion requires BH4, and deficiencies in either the cofactor or the enzyme PAH can result in phenylketonuria. Additionally, the inability to synthesize tyrosine will make this a conditionally essential amino acid and potentially negatively impact the synthesis of downstream compounds illustrated in figure 4.2.', '6778e5ab-6768-4fae-86c7-ee2b6de8164c': 'Tyrosine can be produced from phenylalanine metabolism and is required for the production of melanin and the catecholamines. Deficiencies can occur at several different locations in the pathway and result in albinism (tyrosinase), alkaptonuria (homogentisate oxidase), or tyrosinemia, which can manifest due to deficiencies in several enzymes along the pathway (figure 4.1).'}"
Figure 4.3,neuroscience/images/Figure 4.3.jpg,Figure 4.3: Metabolism of tryptophan to melatonin.,"Tryptophan is an essential amino acid that is both ketogenic and glucogenic as it can be oxidized to produce alanine and acetyl-CoA. The ring structure can also be used to synthesize niacin, reducing the dietary requirement for this vitamin. Tryptophan metabolism to serotonin (and subsequently melatonin) requires BH4. Deficiencies here can lead to imbalances in these neurotransmitters (figure 4.3).","{'dee0215c-7152-4c97-afbd-f0d03484af84': 'Tryptophan is an essential amino acid that is both ketogenic and glucogenic as it can be oxidized to produce alanine and acetyl-CoA. The ring structure can also be used to synthesize niacin, reducing the dietary requirement for this vitamin. Tryptophan metabolism to serotonin (and subsequently melatonin) requires BH4. Deficiencies here can lead to imbalances in these neurotransmitters (figure 4.3).'}"
Figure 4.4,neuroscience/images/Figure 4.4.jpg,Figure 4.4: Glutamate metabolism as it interfaces with nitrogen transport and synthesis of GABA.,"Glutamate plays many key roles in amino acid metabolism and provides substrates for GABA and glutathione synthesis (figure 4.4). Additionally, glutamate plays a role in nitrogen movement within the body. Glutamate can be deaminated by glutamate dehydrogenase to yield α-ketoglutarate. This can enter directly into the TCA cycle or be transaminated (figure 4.4). Additionally, glutamate can be used to fix or free ammonium to generate glutamine—one of the essential, nontoxic carriers of ammonia.","{'62b26cb1-b780-486e-acbc-37dd751b58e7': 'Glutamate plays many key roles in amino acid metabolism and provides substrates for GABA and glutathione synthesis (figure 4.4). Additionally, glutamate plays a role in nitrogen movement within the body. Glutamate can be deaminated by glutamate dehydrogenase to yield α-ketoglutarate. This can enter directly into the TCA cycle or be transaminated (figure 4.4). Additionally, glutamate can be used to fix or free ammonium to generate glutamine—one of the essential, nontoxic carriers of ammonia.', '24801513-7b21-42ef-bf30-32be372bb1f6': 'Glutamate is the most important transmitter for normal brain function. Nearly all excitatory neurons in the central nervous system (CNS) are glutamatergic. Glutamate is a nonessential amino acid that does not cross the blood-brain barrier and therefore must be synthesized in neurons from local precursors. The most prevalent precursor for glutamate synthesis is glutamine, which is taken up into presynaptic terminals by the system A transporter 2 (SAT2) and is then metabolized to glutamate by the mitochondrial enzyme glutaminase (figure 2.3).', '29ebc630-cef4-4261-8494-6ed21b0f0016': 'Glutamate synthesized in the presynaptic cytoplasm is packaged into synaptic vesicles by vesicular glutamate transporters (VGLUTs). Once released, glutamate is removed from the synaptic cleft by the excitatory amino acid transporters (EAATs). EAATs are a family of five different Na+-dependent glutamate cotransporters. Some EAATs are present in glial cells and others in presynaptic terminals. Glutamate transported into glial cells via EAATs is converted into glutamine by the enzyme glutamine synthetase. Glutamine is then transported out of the glial cells by a different transporter, the system N transporter 1 (SN1), and transported into nerve terminals via SAT2. This overall sequence of events is referred to as the glutamate–glutamine cycle. This cycle allows glial cells and presynaptic terminals to cooperate both to maintain an adequate supply of glutamate for synaptic transmission and to rapidly terminate postsynaptic glutamate action (figure 2.4).'}"
Figure 4.6,neuroscience/images/Figure 4.6.jpg,Figure 4.6: Metabolism of methionine. Remethylation and transsulfuration of homocysteine are illustrated. Cofactor or enzymatic deficiencies can result in an elevation of homocysteine.,"Initially, methionine will condense with ATP to form SAM. SAM has a charged methyl group, which can be transferred to many different acceptor molecules; this step is considered irreversible as the amount of energy released is substantial. SAM is used by many biological pathways to donate methyl groups, and it is in consistent demand. After SAM loses its methyl group, the resulting compound, S-adenosylhomocysteine (SAH), is hydrolyzed to homocysteine and adenosine. Homocysteine, generated from this reaction, can either be remethylated in a reaction using both folate and cobalamin to resynthesize methionine or can be used for the synthesis of cysteine (figure 4.6).","{'ae28d1c5-0c2c-4e59-8391-fb88e7d08cb7': 'Methionine is an essential amino acid with a complex metabolism of clinical importance. Its metabolism interfaces with the folate cycle, cobalamin remethylation, and the synthesis of S-adenosylmethionine (SAM). Enzymatic or cofactor deficiencies can result in elevated homocysteine levels (hyperhomocysteinemia), which can have negative impacts systemically. Methionine, required for the synthesis of SAM, can be obtained from the diet or produced from remethylation of homocysteine using vitamin B12.', '95d35415-03a3-49ae-b442-2827f8f346a1': 'Initially, methionine will condense with ATP to form SAM. SAM has a charged methyl group, which can be transferred to many different acceptor molecules; this step is considered irreversible as the amount of energy released is substantial. SAM is used by many biological pathways to donate methyl groups, and it is in consistent demand. After SAM loses its methyl group, the resulting compound, S-adenosylhomocysteine (SAH), is hydrolyzed to homocysteine and adenosine. Homocysteine, generated from this reaction, can either be remethylated in a reaction using both folate and cobalamin to resynthesize methionine or can be used for the synthesis of cysteine (figure 4.6).', '663b595a-3866-4c1a-8f45-92381705bd10': 'Further metabolism of homocysteine provides the sulfur atom for the synthesis of cysteine. In this two-step process, homocysteine first reacts with serine to form cystathionine. This is followed by cleavage of cystathionine, which yields cysteine and α-ketobutyrate. The first reaction in this sequence, catalyzed by cystathionine β-synthase, is inhibited by cysteine. Thus, methionine, via homocysteine, is not used for cysteine synthesis unless the levels of cysteine in the body are lower than required for its metabolic functions. An adequate dietary supply of cysteine, therefore, can “spare” (or reduce) the dietary requirement for methionine (figure 4.6).'}"
Figure 4.6,neuroscience/images/Figure 4.6.jpg,Figure 4.6: Metabolism of methionine. Remethylation and transsulfuration of homocysteine are illustrated. Cofactor or enzymatic deficiencies can result in an elevation of homocysteine.,"Initially, methionine will condense with ATP to form SAM. SAM has a charged methyl group, which can be transferred to many different acceptor molecules; this step is considered irreversible as the amount of energy released is substantial. SAM is used by many biological pathways to donate methyl groups, and it is in consistent demand. After SAM loses its methyl group, the resulting compound, S-adenosylhomocysteine (SAH), is hydrolyzed to homocysteine and adenosine. Homocysteine, generated from this reaction, can either be remethylated in a reaction using both folate and cobalamin to resynthesize methionine or can be used for the synthesis of cysteine (figure 4.6).","{'ae28d1c5-0c2c-4e59-8391-fb88e7d08cb7': 'Methionine is an essential amino acid with a complex metabolism of clinical importance. Its metabolism interfaces with the folate cycle, cobalamin remethylation, and the synthesis of S-adenosylmethionine (SAM). Enzymatic or cofactor deficiencies can result in elevated homocysteine levels (hyperhomocysteinemia), which can have negative impacts systemically. Methionine, required for the synthesis of SAM, can be obtained from the diet or produced from remethylation of homocysteine using vitamin B12.', '95d35415-03a3-49ae-b442-2827f8f346a1': 'Initially, methionine will condense with ATP to form SAM. SAM has a charged methyl group, which can be transferred to many different acceptor molecules; this step is considered irreversible as the amount of energy released is substantial. SAM is used by many biological pathways to donate methyl groups, and it is in consistent demand. After SAM loses its methyl group, the resulting compound, S-adenosylhomocysteine (SAH), is hydrolyzed to homocysteine and adenosine. Homocysteine, generated from this reaction, can either be remethylated in a reaction using both folate and cobalamin to resynthesize methionine or can be used for the synthesis of cysteine (figure 4.6).', '663b595a-3866-4c1a-8f45-92381705bd10': 'Further metabolism of homocysteine provides the sulfur atom for the synthesis of cysteine. In this two-step process, homocysteine first reacts with serine to form cystathionine. This is followed by cleavage of cystathionine, which yields cysteine and α-ketobutyrate. The first reaction in this sequence, catalyzed by cystathionine β-synthase, is inhibited by cysteine. Thus, methionine, via homocysteine, is not used for cysteine synthesis unless the levels of cysteine in the body are lower than required for its metabolic functions. An adequate dietary supply of cysteine, therefore, can “spare” (or reduce) the dietary requirement for methionine (figure 4.6).'}"
Figure 2.1,neuroscience/images/Figure 2.1.jpg,Figure 2.1: Synthesis and degradation of acetylcholine.,"Acetylcholine (ACh) was the first identified neurotransmitter and is synthesized in nerve terminals from the precursors acetyl-CoA and choline, in a reaction catalyzed by choline acetyltransferase (ChAT) (figure 2.1). After synthesis in the cytoplasm of the neuron, a vesicular ACh transporter (VAChT) loads ACh into each cholinergic vesicle. The energy required to concentrate ACh within the vesicle is provided by the acidic pH of the vesicle lumen, which allows the VAChT to exchange H+ for ACh.","{'30504ceb-862e-48c1-bc39-4ebd97e7cd2a': 'Ferrier, D. R., ed. Lippincott Illustrated Reviews: Biochemistry, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017,\xa0 Chapter 20: Amino Acid Degradation and Synthesis, Chapter 21: Conversion of Amino Acids to Specialized Products.', 'f814fbb7-0506-470d-be91-332dc7f6e933': 'Lieberman, M., and A. Peet, eds. Marks’ Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 37: Synthesis and Degradation of Amino Acids, Chapter 39: Tetrahydrofolate, Vitamin B12, and S-Adenosylmethionine.', '279012c4-5337-4f17-8e30-15c0a30fd0c7': 'Le, T., and V. Bhushan.\xa0First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 69, 83–85.', '1cb43208-8a51-4579-9c86-2ac4863a85bd': 'Peptide-secreting neurons generally synthesize polypeptides that are much larger than the final, “mature” peptide. Processing these polypeptides, which are called pre-propeptides, takes place within the neuron’s cell body by a sequence of reactions that occur in several intracellular organelles. Pre-propeptides are synthesized in the rough endoplasmic reticulum, where the signal sequence—that is, the sequence of amino acids indicating that the peptide is to be secreted—is removed. The remaining polypeptide,\xa0referred to as the propeptide, moves through the Golgi apparatus and is packaged into vesicles in the trans-Golgi network. The final stages of peptide neurotransmitter processing\xa0involve\xa0proteolytic cleavage and occur\xa0within the Golgi-associated vesicles.\xa0In addition to cleavage,\xa0modification of the ends of the peptide by glycosylation, phosphorylation, and disulfide bond formation is also common.', '43721d34-b597-459d-9a11-fed27bc8628c': 'Purves, D., G. J. Augustine, Dd. Fitzpatrick, L. C. Katz, A.-S. LaMantia, J. O. McNamara, and S. M. Williams, eds. Neuroscience, 2nd ed. Sunderland, MA: Sinauer Associates, 2001, Chapter 6: Neurotransmitters.', '474c3f8f-b2a3-4c5e-bac4-e6ab9d814896': 'Acetylcholine (ACh) was the first identified neurotransmitter and is synthesized in nerve terminals from the precursors acetyl-CoA\xa0and choline, in a reaction catalyzed by choline acetyltransferase (ChAT) (figure 2.1). After synthesis in the cytoplasm of the neuron, a vesicular ACh transporter (VAChT) loads ACh into each cholinergic vesicle. The energy required to concentrate ACh within the vesicle is provided by the acidic pH of the vesicle lumen, which allows the VAChT to exchange H+ for ACh.', '3ef1c28b-edf3-4c7d-8cfe-98104a3884de': '“Biochemistry of Nerve Transmission.” The Medical Biochemistry Page. http://themedicalbiochemistrypage.or…-transmission/.', '5f067d1d-a9fe-42d5-ba5d-00d875139d3a': '“Neurotransmitters and Receptors: Different Classes of Neurotransmitters, and Different Types of Receptors They Bind To.” Khan Academy. https://www.khanacademy.org/science/…heir-receptors.', '54b79b2a-82e4-4d60-8931-2b5fd438204d': 'As a brief review, glucose is taken up by the brain in an insulin-independent manner. The brain oxidizes glucose under most conditions with the exception of starvation states. Once the glucose is phosphorylated to glucose 6-phosphate (by hexokinase), it has three potential fates (figure 1.1):', '0babe716-7b82-4f49-b785-4b7efcc7d5d3': 'What is unique to the brain\xa0is that not all cell types\xa0oxidize glucose to the same extent, but\xa0there is a tight coupling that exists between cell types to support both energy demand and glutamate-mediated neurotransmission. This compartmentalized, coupled metabolism between neurons and astrocytes\xa0is essential for ATP production, neuronal excitability, and adaptations to stress.', '3657c3ea-7aa2-4b93-85f4-ab8eca86a4d2': 'In the context of this chapter, oxidative metabolism refers to the oxidation of a substrate (glucose) through mitochondrial metabolism versus\xa0glycolytic metabolism, which refers to the oxidation of glucose to lactate.', '3582281d-f4e1-4294-88e1-0f77fae600ed': 'To support the high energy demands imposed on neurons, they sustain a high rate of oxidative metabolism for ATP production compared to astrocytes. Despite this high rate of mitochondrial metabolism, glucose uptake is reduced when compared to astrocytes, in part due to the use of lactate as an energy source. Neurons show a preference for lactate over glucose when both substrates are present. There are several reasons why sustaining a low glycolytic rate but high oxidative rate is preferred in this tissue:', '977f700d-dda5-42c2-ab14-a789271e1739': 'To accommodate these two processes, neurons preferentially utilize lactate, which can be readily converted to pyruvate and enter the mitochondria (figure 1.2). The lactate required for neuronal metabolism is produced by astrocytic glucose oxidation and is discussed below.', 'cd766723-9078-4cfe-a5af-7e26de693949': 'Bélanger, M., I. Allaman, and P. J. Magistretti. “Brain Energy Metabolism: Focus on Astrocyte–Neuron Metabolic Cooperation.” Cell Metabolism 14, no. 6 (December 2011): 724–738, https://doi.org/10.1016/j.cmet.2011.08.016.', '7fd59828-b121-4cf5-9bf5-3e7779c2360c': 'Le, T., and V. Bhushan.\xa0First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 87, 314–315.', 'c3528409-5aee-410f-81f0-443b61264194': 'Lieberman, M., and A. Peet, eds. Marks’ Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 46: Metabolism of the Nervous System.', '66a8b8c3-3424-4336-9832-393bb4d42d51': 'Magistretti, P. J., and I. Allaman. “A Cellular Perspective on Brain Energy Metabolism and Functional Imaging.” Neuron 86, no. 4 (May 2015): 883–901, https://doi.org/10.1016/j.neuron.2015.03.035.', 'daac396d-a353-40f3-a508-88eaa6a86b43': 'In contrast to most other small-molecule neurotransmitters, the postsynaptic actions of ACh are not terminated by reuptake but hydrolysis by acetylcholinesterase (AChE). This enzyme is concentrated in the synaptic cleft, ensuring a rapid decrease in ACh concentration after its release from the presynaptic terminal. The hydrolysis results in acetate and choline (figure 2.1), which is recycled by being transported back into nerve terminals, where it is used to resynthesize ACh. Organophosphates are one class of drugs known to interact with ACh signal transmission through the inhibition of AChE, allowing ACh to accumulate at cholinergic synapses. This buildup of ACh depolarizes the postsynaptic muscle cell and renders it refractory to subsequent ACh release, causing neuromuscular paralysis.'}"
Figure 2.1,neuroscience/images/Figure 2.1.jpg,Figure 2.1: Synthesis and degradation of acetylcholine.,"Acetylcholine (ACh) was the first identified neurotransmitter and is synthesized in nerve terminals from the precursors acetyl-CoA and choline, in a reaction catalyzed by choline acetyltransferase (ChAT) (figure 2.1). After synthesis in the cytoplasm of the neuron, a vesicular ACh transporter (VAChT) loads ACh into each cholinergic vesicle. The energy required to concentrate ACh within the vesicle is provided by the acidic pH of the vesicle lumen, which allows the VAChT to exchange H+ for ACh.","{'30504ceb-862e-48c1-bc39-4ebd97e7cd2a': 'Ferrier, D. R., ed. Lippincott Illustrated Reviews: Biochemistry, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017,\xa0 Chapter 20: Amino Acid Degradation and Synthesis, Chapter 21: Conversion of Amino Acids to Specialized Products.', 'f814fbb7-0506-470d-be91-332dc7f6e933': 'Lieberman, M., and A. Peet, eds. Marks’ Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 37: Synthesis and Degradation of Amino Acids, Chapter 39: Tetrahydrofolate, Vitamin B12, and S-Adenosylmethionine.', '279012c4-5337-4f17-8e30-15c0a30fd0c7': 'Le, T., and V. Bhushan.\xa0First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 69, 83–85.', '1cb43208-8a51-4579-9c86-2ac4863a85bd': 'Peptide-secreting neurons generally synthesize polypeptides that are much larger than the final, “mature” peptide. Processing these polypeptides, which are called pre-propeptides, takes place within the neuron’s cell body by a sequence of reactions that occur in several intracellular organelles. Pre-propeptides are synthesized in the rough endoplasmic reticulum, where the signal sequence—that is, the sequence of amino acids indicating that the peptide is to be secreted—is removed. The remaining polypeptide,\xa0referred to as the propeptide, moves through the Golgi apparatus and is packaged into vesicles in the trans-Golgi network. The final stages of peptide neurotransmitter processing\xa0involve\xa0proteolytic cleavage and occur\xa0within the Golgi-associated vesicles.\xa0In addition to cleavage,\xa0modification of the ends of the peptide by glycosylation, phosphorylation, and disulfide bond formation is also common.', '43721d34-b597-459d-9a11-fed27bc8628c': 'Purves, D., G. J. Augustine, Dd. Fitzpatrick, L. C. Katz, A.-S. LaMantia, J. O. McNamara, and S. M. Williams, eds. Neuroscience, 2nd ed. Sunderland, MA: Sinauer Associates, 2001, Chapter 6: Neurotransmitters.', '474c3f8f-b2a3-4c5e-bac4-e6ab9d814896': 'Acetylcholine (ACh) was the first identified neurotransmitter and is synthesized in nerve terminals from the precursors acetyl-CoA\xa0and choline, in a reaction catalyzed by choline acetyltransferase (ChAT) (figure 2.1). After synthesis in the cytoplasm of the neuron, a vesicular ACh transporter (VAChT) loads ACh into each cholinergic vesicle. The energy required to concentrate ACh within the vesicle is provided by the acidic pH of the vesicle lumen, which allows the VAChT to exchange H+ for ACh.', '3ef1c28b-edf3-4c7d-8cfe-98104a3884de': '“Biochemistry of Nerve Transmission.” The Medical Biochemistry Page. http://themedicalbiochemistrypage.or…-transmission/.', '5f067d1d-a9fe-42d5-ba5d-00d875139d3a': '“Neurotransmitters and Receptors: Different Classes of Neurotransmitters, and Different Types of Receptors They Bind To.” Khan Academy. https://www.khanacademy.org/science/…heir-receptors.', '54b79b2a-82e4-4d60-8931-2b5fd438204d': 'As a brief review, glucose is taken up by the brain in an insulin-independent manner. The brain oxidizes glucose under most conditions with the exception of starvation states. Once the glucose is phosphorylated to glucose 6-phosphate (by hexokinase), it has three potential fates (figure 1.1):', '0babe716-7b82-4f49-b785-4b7efcc7d5d3': 'What is unique to the brain\xa0is that not all cell types\xa0oxidize glucose to the same extent, but\xa0there is a tight coupling that exists between cell types to support both energy demand and glutamate-mediated neurotransmission. This compartmentalized, coupled metabolism between neurons and astrocytes\xa0is essential for ATP production, neuronal excitability, and adaptations to stress.', '3657c3ea-7aa2-4b93-85f4-ab8eca86a4d2': 'In the context of this chapter, oxidative metabolism refers to the oxidation of a substrate (glucose) through mitochondrial metabolism versus\xa0glycolytic metabolism, which refers to the oxidation of glucose to lactate.', '3582281d-f4e1-4294-88e1-0f77fae600ed': 'To support the high energy demands imposed on neurons, they sustain a high rate of oxidative metabolism for ATP production compared to astrocytes. Despite this high rate of mitochondrial metabolism, glucose uptake is reduced when compared to astrocytes, in part due to the use of lactate as an energy source. Neurons show a preference for lactate over glucose when both substrates are present. There are several reasons why sustaining a low glycolytic rate but high oxidative rate is preferred in this tissue:', '977f700d-dda5-42c2-ab14-a789271e1739': 'To accommodate these two processes, neurons preferentially utilize lactate, which can be readily converted to pyruvate and enter the mitochondria (figure 1.2). The lactate required for neuronal metabolism is produced by astrocytic glucose oxidation and is discussed below.', 'cd766723-9078-4cfe-a5af-7e26de693949': 'Bélanger, M., I. Allaman, and P. J. Magistretti. “Brain Energy Metabolism: Focus on Astrocyte–Neuron Metabolic Cooperation.” Cell Metabolism 14, no. 6 (December 2011): 724–738, https://doi.org/10.1016/j.cmet.2011.08.016.', '7fd59828-b121-4cf5-9bf5-3e7779c2360c': 'Le, T., and V. Bhushan.\xa0First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 87, 314–315.', 'c3528409-5aee-410f-81f0-443b61264194': 'Lieberman, M., and A. Peet, eds. Marks’ Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 46: Metabolism of the Nervous System.', '66a8b8c3-3424-4336-9832-393bb4d42d51': 'Magistretti, P. J., and I. Allaman. “A Cellular Perspective on Brain Energy Metabolism and Functional Imaging.” Neuron 86, no. 4 (May 2015): 883–901, https://doi.org/10.1016/j.neuron.2015.03.035.', 'daac396d-a353-40f3-a508-88eaa6a86b43': 'In contrast to most other small-molecule neurotransmitters, the postsynaptic actions of ACh are not terminated by reuptake but hydrolysis by acetylcholinesterase (AChE). This enzyme is concentrated in the synaptic cleft, ensuring a rapid decrease in ACh concentration after its release from the presynaptic terminal. The hydrolysis results in acetate and choline (figure 2.1), which is recycled by being transported back into nerve terminals, where it is used to resynthesize ACh. Organophosphates are one class of drugs known to interact with ACh signal transmission through the inhibition of AChE, allowing ACh to accumulate at cholinergic synapses. This buildup of ACh depolarizes the postsynaptic muscle cell and renders it refractory to subsequent ACh release, causing neuromuscular paralysis.'}"
Figure 2.2,neuroscience/images/Figure 2.2.jpg,Figure 2.2: ACh release and degradation. (A: acetyl-CoA; ACh: acetylcholine; AChE: acetylcholine esterase; Ch: choline; VAChT: vesicular ACh transporter),"A second class of ACh receptors are referred to as muscarinic ACh receptors (mAChRs). mAChRs are metabotropic and mediate most of the effects of ACh in the brain. Like other metabotropic receptors, mAChRs have seven helical membrane-spanning domains. Binding of ACh to the receptor causes a conformational change that permits G-proteins to bind to the cytoplasmic domain of the mAChR (figure 2.2).","{'b4795726-a834-453a-bfea-985baa8478e5': 'Many of the postsynaptic actions of ACh are mediated by the nicotinic ACh receptor (nAChR). nAChRs are nonselective cation channels that generate excitatory postsynaptic responses. Nicotinic receptors are large protein complexes consisting of five subunits. At the neuromuscular junction, the nAChR contains two α subunits, each of which has a binding site that binds a single molecule of ACh. Both ACh binding sites must be occupied for the receptor to be activated. In summary, the nAChR is a ligand-gated ion channel.', '538f2a7f-1632-46c2-8cb1-748638bca19a': 'A second class of ACh receptors are referred to as muscarinic ACh receptors (mAChRs). mAChRs are metabotropic and mediate most of the effects of ACh in the brain. Like other metabotropic receptors, mAChRs have seven helical membrane-spanning domains. Binding of ACh to the receptor causes a conformational change that permits G-proteins to bind to the cytoplasmic domain of the mAChR (figure 2.2).'}"
Figure 2.3,neuroscience/images/Figure 2.3.jpg,Figure 2.3: Glutamate and GABA synthesis. (α-KG: α-ketoglutarate; PLP: pyridoxal phosphate),"Glutamate is the most important transmitter for normal brain function. Nearly all excitatory neurons in the central nervous system (CNS) are glutamatergic. Glutamate is a nonessential amino acid that does not cross the blood-brain barrier and therefore must be synthesized in neurons from local precursors. The most prevalent precursor for glutamate synthesis is glutamine, which is taken up into presynaptic terminals by the system A transporter 2 (SAT2) and is then metabolized to glutamate by the mitochondrial enzyme glutaminase (figure 2.3).","{'62b26cb1-b780-486e-acbc-37dd751b58e7': 'Glutamate plays many key roles in amino acid metabolism and provides substrates for GABA and glutathione synthesis (figure 4.4). Additionally, glutamate plays a role in nitrogen movement within the body. Glutamate can be deaminated by glutamate dehydrogenase to yield α-ketoglutarate. This can enter directly into the TCA cycle or be transaminated (figure 4.4). Additionally, glutamate can be used to fix or free ammonium to generate glutamine—one of the essential, nontoxic carriers of ammonia.', '24801513-7b21-42ef-bf30-32be372bb1f6': 'Glutamate is the most important transmitter for normal brain function. Nearly all excitatory neurons in the central nervous system (CNS) are glutamatergic. Glutamate is a nonessential amino acid that does not cross the blood-brain barrier and therefore must be synthesized in neurons from local precursors. The most prevalent precursor for glutamate synthesis is glutamine, which is taken up into presynaptic terminals by the system A transporter 2 (SAT2) and is then metabolized to glutamate by the mitochondrial enzyme glutaminase (figure 2.3).', '29ebc630-cef4-4261-8494-6ed21b0f0016': 'Glutamate synthesized in the presynaptic cytoplasm is packaged into synaptic vesicles by vesicular glutamate transporters (VGLUTs). Once released, glutamate is removed from the synaptic cleft by the excitatory amino acid transporters (EAATs). EAATs are a family of five different Na+-dependent glutamate cotransporters. Some EAATs are present in glial cells and others in presynaptic terminals. Glutamate transported into glial cells via EAATs is converted into glutamine by the enzyme glutamine synthetase. Glutamine is then transported out of the glial cells by a different transporter, the system N transporter 1 (SN1), and transported into nerve terminals via SAT2. This overall sequence of events is referred to as the glutamate–glutamine cycle. This cycle allows glial cells and presynaptic terminals to cooperate both to maintain an adequate supply of glutamate for synaptic transmission and to rapidly terminate postsynaptic glutamate action (figure 2.4).', '466eee53-4364-44de-87f8-c625fdb6645f': 'Most inhibitory synapses in the brain and spinal cord use either γ-aminobutyric acid (GABA) or glycine as neurotransmitters. The predominant precursor for GABA synthesis is glucose, which is metabolized to glutamate by the tricarboxylic acid cycle enzymes (figure 2.3). The enzyme glutamic acid decarboxylase (GAD), which is found almost exclusively in GABAergic neurons, catalyzes the conversion of glutamate to GABA. GAD requires pyridoxal phosphate for activity; a deficiency of this vitamin can lead to diminished GABA synthesis.', '0d07f0a5-5274-46d6-a874-1e7b049c9f4f': 'Once GABA is synthesized, it is transported into synaptic vesicles via a vesicular inhibitory amino acid transporter (VIAAT). The mechanism of GABA removal is similar to that of glutamate. Both neurons and glia contain high-affinity Na+-dependent cotransporters for GABA, and these cotransporters are termed GATs. Most GABA is eventually converted to succinate, which is metabolized further in the tricarboxylic acid cycle that mediates cellular ATP synthesis.', '390b60b9-a56a-4cd8-ab99-9d8ee6bf9d47': 'Two mitochondrial enzymes are required for this degradation: GABA transaminase and succinic semialdehyde dehydrogenase.'}"
Figure 2.4,neuroscience/images/Figure 2.4.jpg,Figure 2.4: Glutamate release and reuptake. (EAAT: excitatory amino acid transporters),"Glutamate synthesized in the presynaptic cytoplasm is packaged into synaptic vesicles by vesicular glutamate transporters (VGLUTs). Once released, glutamate is removed from the synaptic cleft by the excitatory amino acid transporters (EAATs). EAATs are a family of five different Na+-dependent glutamate cotransporters. Some EAATs are present in glial cells and others in presynaptic terminals. Glutamate transported into glial cells via EAATs is converted into glutamine by the enzyme glutamine synthetase. Glutamine is then transported out of the glial cells by a different transporter, the system N transporter 1 (SN1), and transported into nerve terminals via SAT2. This overall sequence of events is referred to as the glutamate–glutamine cycle. This cycle allows glial cells and presynaptic terminals to cooperate both to maintain an adequate supply of glutamate for synaptic transmission and to rapidly terminate postsynaptic glutamate action (figure 2.4).","{'62b26cb1-b780-486e-acbc-37dd751b58e7': 'Glutamate plays many key roles in amino acid metabolism and provides substrates for GABA and glutathione synthesis (figure 4.4). Additionally, glutamate plays a role in nitrogen movement within the body. Glutamate can be deaminated by glutamate dehydrogenase to yield α-ketoglutarate. This can enter directly into the TCA cycle or be transaminated (figure 4.4). Additionally, glutamate can be used to fix or free ammonium to generate glutamine—one of the essential, nontoxic carriers of ammonia.', '24801513-7b21-42ef-bf30-32be372bb1f6': 'Glutamate is the most important transmitter for normal brain function. Nearly all excitatory neurons in the central nervous system (CNS) are glutamatergic. Glutamate is a nonessential amino acid that does not cross the blood-brain barrier and therefore must be synthesized in neurons from local precursors. The most prevalent precursor for glutamate synthesis is glutamine, which is taken up into presynaptic terminals by the system A transporter 2 (SAT2) and is then metabolized to glutamate by the mitochondrial enzyme glutaminase (figure 2.3).', '29ebc630-cef4-4261-8494-6ed21b0f0016': 'Glutamate synthesized in the presynaptic cytoplasm is packaged into synaptic vesicles by vesicular glutamate transporters (VGLUTs). Once released, glutamate is removed from the synaptic cleft by the excitatory amino acid transporters (EAATs). EAATs are a family of five different Na+-dependent glutamate cotransporters. Some EAATs are present in glial cells and others in presynaptic terminals. Glutamate transported into glial cells via EAATs is converted into glutamine by the enzyme glutamine synthetase. Glutamine is then transported out of the glial cells by a different transporter, the system N transporter 1 (SN1), and transported into nerve terminals via SAT2. This overall sequence of events is referred to as the glutamate–glutamine cycle. This cycle allows glial cells and presynaptic terminals to cooperate both to maintain an adequate supply of glutamate for synaptic transmission and to rapidly terminate postsynaptic glutamate action (figure 2.4).'}"
Figure 2.3,neuroscience/images/Figure 2.3.jpg,Figure 2.3: Glutamate and GABA synthesis. (α-KG: α-ketoglutarate; PLP: pyridoxal phosphate),"Glutamate is the most important transmitter for normal brain function. Nearly all excitatory neurons in the central nervous system (CNS) are glutamatergic. Glutamate is a nonessential amino acid that does not cross the blood-brain barrier and therefore must be synthesized in neurons from local precursors. The most prevalent precursor for glutamate synthesis is glutamine, which is taken up into presynaptic terminals by the system A transporter 2 (SAT2) and is then metabolized to glutamate by the mitochondrial enzyme glutaminase (figure 2.3).","{'62b26cb1-b780-486e-acbc-37dd751b58e7': 'Glutamate plays many key roles in amino acid metabolism and provides substrates for GABA and glutathione synthesis (figure 4.4). Additionally, glutamate plays a role in nitrogen movement within the body. Glutamate can be deaminated by glutamate dehydrogenase to yield α-ketoglutarate. This can enter directly into the TCA cycle or be transaminated (figure 4.4). Additionally, glutamate can be used to fix or free ammonium to generate glutamine—one of the essential, nontoxic carriers of ammonia.', '24801513-7b21-42ef-bf30-32be372bb1f6': 'Glutamate is the most important transmitter for normal brain function. Nearly all excitatory neurons in the central nervous system (CNS) are glutamatergic. Glutamate is a nonessential amino acid that does not cross the blood-brain barrier and therefore must be synthesized in neurons from local precursors. The most prevalent precursor for glutamate synthesis is glutamine, which is taken up into presynaptic terminals by the system A transporter 2 (SAT2) and is then metabolized to glutamate by the mitochondrial enzyme glutaminase (figure 2.3).', '29ebc630-cef4-4261-8494-6ed21b0f0016': 'Glutamate synthesized in the presynaptic cytoplasm is packaged into synaptic vesicles by vesicular glutamate transporters (VGLUTs). Once released, glutamate is removed from the synaptic cleft by the excitatory amino acid transporters (EAATs). EAATs are a family of five different Na+-dependent glutamate cotransporters. Some EAATs are present in glial cells and others in presynaptic terminals. Glutamate transported into glial cells via EAATs is converted into glutamine by the enzyme glutamine synthetase. Glutamine is then transported out of the glial cells by a different transporter, the system N transporter 1 (SN1), and transported into nerve terminals via SAT2. This overall sequence of events is referred to as the glutamate–glutamine cycle. This cycle allows glial cells and presynaptic terminals to cooperate both to maintain an adequate supply of glutamate for synaptic transmission and to rapidly terminate postsynaptic glutamate action (figure 2.4).', '466eee53-4364-44de-87f8-c625fdb6645f': 'Most inhibitory synapses in the brain and spinal cord use either γ-aminobutyric acid (GABA) or glycine as neurotransmitters. The predominant precursor for GABA synthesis is glucose, which is metabolized to glutamate by the tricarboxylic acid cycle enzymes (figure 2.3). The enzyme glutamic acid decarboxylase (GAD), which is found almost exclusively in GABAergic neurons, catalyzes the conversion of glutamate to GABA. GAD requires pyridoxal phosphate for activity; a deficiency of this vitamin can lead to diminished GABA synthesis.', '0d07f0a5-5274-46d6-a874-1e7b049c9f4f': 'Once GABA is synthesized, it is transported into synaptic vesicles via a vesicular inhibitory amino acid transporter (VIAAT). The mechanism of GABA removal is similar to that of glutamate. Both neurons and glia contain high-affinity Na+-dependent cotransporters for GABA, and these cotransporters are termed GATs. Most GABA is eventually converted to succinate, which is metabolized further in the tricarboxylic acid cycle that mediates cellular ATP synthesis.', '390b60b9-a56a-4cd8-ab99-9d8ee6bf9d47': 'Two mitochondrial enzymes are required for this degradation: GABA transaminase and succinic semialdehyde dehydrogenase.'}"
Figure 2.5,neuroscience/images/Figure 2.5.jpg,Figure 2.5: GABA and glycine release.  (GAT: cotransporters for GABA; VIAAT: vesicular inhibitory amino acid transporter),The distribution of the neutral amino acid glycine in the CNS is more restricted than that of GABA. About half of the inhibitory synapses in the spinal cord use glycine; most other inhibitory synapses use GABA. Glycine is synthesized from serine by the mitochondrial isoform of serine hydroxymethyltransferase (figure 2.5) and is transported into synaptic vesicles via the same VIAAT that loads GABA into vesicles.,"{'ec1d3db9-6247-462a-aea3-c2d048bf6d68': 'Glycine is a key compound that functions as an essential substrate for various pathways, including the folate cycle, nucleotide synthesis, and synthesis of porphyrins (heme), glutathione, and creatine.', '4212e1fe-4eb0-4274-8994-9aaa32a0ac9e': 'The distribution of the neutral amino acid glycine in the CNS is more restricted than that of GABA. About half of the inhibitory synapses in the spinal cord use glycine; most other inhibitory synapses use GABA. Glycine is synthesized from serine by the mitochondrial isoform of serine hydroxymethyltransferase (figure 2.5) and is transported into synaptic vesicles via the same VIAAT that loads GABA into vesicles.', '229898ad-c1e5-4519-8ca6-64b198787192': 'Once released from the presynaptic cell, glycine is rapidly removed from the synaptic cleft by glycine transporters in the plasma membrane (figure 2.5).'}"
Figure 2.6,neuroscience/images/Figure 2.6.jpg,"Figure 2.6: Synthesis of dopamine, norepinephrine, and epinephrine.",The first step in catecholamine synthesis is catalyzed by tyrosine hydroxylase in a reaction requiring oxygen as a cosubstrate and tetrahydrobiopterin as a cofactor to synthesize dihydroxyphenylalanine (DOPA) (figure 2.6).,"{'1343fada-6249-4ba2-85b9-6d268bb14384': 'The first step in catecholamine synthesis is catalyzed by tyrosine hydroxylase in a reaction requiring oxygen as a cosubstrate and tetrahydrobiopterin as a cofactor to synthesize dihydroxyphenylalanine (DOPA) (figure 2.6).', '3df319ec-e98d-4f4e-9ad7-3a586e4ed1be': 'Dopamine is produced by the action of DOPA decarboxylase on DOPA. Following its synthesis in the cytoplasm of presynaptic terminals, dopamine is loaded into synaptic vesicles via a vesicular monoamine transporter (VMAT). Dopamine action in the synaptic cleft is terminated by reuptake of dopamine into nerve terminals or surrounding glial cells by a Na+-dependent dopamine cotransporter, termed DAT.', 'a38098f7-94bb-4ac9-a774-556ebf5eb182': 'The two major enzymes involved in the catabolism of dopamine are monoamine oxidase (MAO) and catechol O-methyltransferase (COMT). Both neurons and glia contain mitochondrial MAO and cytoplasmic COMT.', 'b51a4662-9d6c-42f2-83fc-8ad2d6beb3a9': 'Once released, dopamine acts exclusively by activating G-protein–coupled receptors. Most dopamine receptor subtypes act by either activating or inhibiting adenylyl cyclase. Activation of these receptors generally contributes to complex behaviors.', '8c9edc66-b93d-4f3e-9f1f-a979b14aa20d': 'Norepinephrine (also called noradrenaline) is used as a neurotransmitter and influences sleep and wakefulness, arousal, attention, and feeding behavior. Perhaps the most prominent noradrenergic neurons are sympathetic ganglion cells, which employ norepinephrine as the major peripheral transmitter in this division of the visceral motor system.', '4905d479-d447-48e6-91eb-1513a0b1325b': 'Norepinephrine synthesis requires dopamine β-hydroxylase, which catalyzes the production of norepinephrine from dopamine (figure 2.6). Norepinephrine is then loaded into synaptic vesicles via the same VMAT involved in vesicular dopamine transport.', 'e6fd5437-7024-4040-bbee-425be9e19a84': 'Norepinephrine is cleared from the synaptic cleft by the norepinephrine transporter (NET), an Na+-dependent cotransporter that is also capable of taking up dopamine. NET is a molecular target of amphetamine, which acts as a stimulant by producing a net increase in the release of norepinephrine and dopamine. Like dopamine, norepinephrine is degraded by MAO and COMT.', 'd1119468-0f78-46ff-94d8-79d9bf3202e0': 'Epinephrine (also called adrenaline) is found in the brain at lower levels than the other catecholamines and is also present in fewer brain neurons than other catecholamines. Epinephrine-secreting neurons regulate respiration and cardiac function. The enzyme that synthesizes epinephrine, phenylethanolamine-N-methyltransferase (figure 2.6), is present only in epinephrine-secreting neurons. Otherwise, the metabolism of epinephrine is very similar to that of norepinephrine. Epinephrine is loaded into vesicles via the VMAT. No plasma membrane transporter specific for epinephrine has been identified, although the NET is capable of transporting epinephrine. As already noted, epinephrine acts on both α- and β-adrenergic receptors.'}"
Figure 2.6,neuroscience/images/Figure 2.6.jpg,"Figure 2.6: Synthesis of dopamine, norepinephrine, and epinephrine.",The first step in catecholamine synthesis is catalyzed by tyrosine hydroxylase in a reaction requiring oxygen as a cosubstrate and tetrahydrobiopterin as a cofactor to synthesize dihydroxyphenylalanine (DOPA) (figure 2.6).,"{'1343fada-6249-4ba2-85b9-6d268bb14384': 'The first step in catecholamine synthesis is catalyzed by tyrosine hydroxylase in a reaction requiring oxygen as a cosubstrate and tetrahydrobiopterin as a cofactor to synthesize dihydroxyphenylalanine (DOPA) (figure 2.6).', '3df319ec-e98d-4f4e-9ad7-3a586e4ed1be': 'Dopamine is produced by the action of DOPA decarboxylase on DOPA. Following its synthesis in the cytoplasm of presynaptic terminals, dopamine is loaded into synaptic vesicles via a vesicular monoamine transporter (VMAT). Dopamine action in the synaptic cleft is terminated by reuptake of dopamine into nerve terminals or surrounding glial cells by a Na+-dependent dopamine cotransporter, termed DAT.', 'a38098f7-94bb-4ac9-a774-556ebf5eb182': 'The two major enzymes involved in the catabolism of dopamine are monoamine oxidase (MAO) and catechol O-methyltransferase (COMT). Both neurons and glia contain mitochondrial MAO and cytoplasmic COMT.', 'b51a4662-9d6c-42f2-83fc-8ad2d6beb3a9': 'Once released, dopamine acts exclusively by activating G-protein–coupled receptors. Most dopamine receptor subtypes act by either activating or inhibiting adenylyl cyclase. Activation of these receptors generally contributes to complex behaviors.', '8c9edc66-b93d-4f3e-9f1f-a979b14aa20d': 'Norepinephrine (also called noradrenaline) is used as a neurotransmitter and influences sleep and wakefulness, arousal, attention, and feeding behavior. Perhaps the most prominent noradrenergic neurons are sympathetic ganglion cells, which employ norepinephrine as the major peripheral transmitter in this division of the visceral motor system.', '4905d479-d447-48e6-91eb-1513a0b1325b': 'Norepinephrine synthesis requires dopamine β-hydroxylase, which catalyzes the production of norepinephrine from dopamine (figure 2.6). Norepinephrine is then loaded into synaptic vesicles via the same VMAT involved in vesicular dopamine transport.', 'e6fd5437-7024-4040-bbee-425be9e19a84': 'Norepinephrine is cleared from the synaptic cleft by the norepinephrine transporter (NET), an Na+-dependent cotransporter that is also capable of taking up dopamine. NET is a molecular target of amphetamine, which acts as a stimulant by producing a net increase in the release of norepinephrine and dopamine. Like dopamine, norepinephrine is degraded by MAO and COMT.', 'd1119468-0f78-46ff-94d8-79d9bf3202e0': 'Epinephrine (also called adrenaline) is found in the brain at lower levels than the other catecholamines and is also present in fewer brain neurons than other catecholamines. Epinephrine-secreting neurons regulate respiration and cardiac function. The enzyme that synthesizes epinephrine, phenylethanolamine-N-methyltransferase (figure 2.6), is present only in epinephrine-secreting neurons. Otherwise, the metabolism of epinephrine is very similar to that of norepinephrine. Epinephrine is loaded into vesicles via the VMAT. No plasma membrane transporter specific for epinephrine has been identified, although the NET is capable of transporting epinephrine. As already noted, epinephrine acts on both α- and β-adrenergic receptors.'}"
Figure 2.7,neuroscience/images/Figure 2.7.jpg,Figure 2.7: Histamine synthesis.,Histamine is produced from the amino acid histidine by a histidine decarboxylase (figure 2.7) and is transported into vesicles via the same VMAT as the catecholamines. No plasma membrane histamine transporter has been identified yet.,"{'57619371-622c-42a4-b61d-b66dd30f7e78': 'Histamine is found in neurons in the hypothalamus that send sparse but widespread projections to almost all regions of the brain and spinal cord. The central histamine projections mediate arousal and attention, similar to central ACh and norepinephrine projections. Histamine also controls the reactivity of the vestibular system. Allergic reactions or tissue damage cause release of histamine from mast cells in the bloodstream. The close proximity of mast cells to blood vessels, together with the potent actions of histamine on blood vessels, raises the possibility that histamine may influence brain blood flow.', '9cdc0fc7-1e2a-42cc-a225-35628c099e68': 'Histamine is produced from the amino acid histidine by a histidine decarboxylase (figure 2.7) and is transported into vesicles via the same VMAT as the catecholamines. No plasma membrane histamine transporter has been identified yet.', '4a5380aa-826d-4eb9-93be-8100dc1c8b53': 'Histamine is degraded by the combined actions of histamine methyltransferase and MAO.'}"
Figure 2.8,neuroscience/images/Figure 2.8.jpg,Figure 2.8: Histamine release and reuptake. (ALDH: aldehyde dehydrogenase; DAO: diamine oxidase; HA: histamine; HNMT: N-methyltransferase; IA: imidazole acetaldehyde; IAA: imidazoleacetic acid; IAAR: imidazoleacetic acid riboside; NMH: N-methylhistamine; N-MIA: methylimidazole acetaldehyde; N-MIAA: N-methylimidazoleacetic acetic acid; OC3: organic cation transporter 3; PMAT: plasma membrane monoamine transporter),"The four known types of histamine receptors are all metabotropic receptors.  Of the four, only two of the receptors (H1 and H2) are well characterized.  Because of the role of histamine receptors in mediating allergic responses, many histamine receptor antagonists have been developed as antihistamine agents. Antihistamines that cross the blood-brain barrier, such as diphenhydramine (Benadryl), act as sedatives by interfering with the roles of histamine in CNS arousal. Antagonists of the H1 receptor also are used to prevent motion sickness, perhaps because of the role of histamine in controlling vestibular function (figure 2.8).","{'3367e478-afe0-4f1b-b8fe-c437ce6a7ba8': 'The four known types of histamine receptors are all metabotropic receptors.\xa0 Of the four, only two of the receptors (H1 and H2) are well characterized.\xa0\xa0Because of the role of histamine receptors in mediating allergic responses, many histamine receptor antagonists have been developed as antihistamine agents. Antihistamines that cross the blood-brain barrier, such as diphenhydramine (Benadryl), act as sedatives by interfering with the roles of histamine in CNS arousal. Antagonists of the H1 receptor also are used to prevent motion sickness, perhaps because of the role of histamine in controlling vestibular function (figure 2.8).', '21cfb848-a6ba-4241-b66b-0f28a292c8ca': 'H2 receptors control the secretion of gastric acid in the digestive system, allowing H2 receptor antagonists to be used in treating a variety of upper gastrointestinal disorders (e.g., peptic ulcers).'}"
Figure 2.9,neuroscience/images/Figure 2.9.jpg,Figure 2.9: Serotonin synthesis.,"Serotonin, or 5-hydroxytryptamine (5-HT), was initially thought to increase vascular tone by virtue of its presence in blood serum (hence the name serotonin). 5-HT is synthesized from the amino acid tryptophan, which is an essential dietary requirement. Tryptophan is taken up into neurons by a plasma membrane transporter and hydroxylated in a reaction catalyzed by the enzyme tryptophan-5-hydroxylase (figure 2.9), the rate-limiting step for 5-HT synthesis. Loading of 5-HT into synaptic vesicles is done by the VMAT that is also responsible for loading other monoamines into synaptic vesicles. The synaptic effects of serotonin are terminated by transport back into nerve terminals via a specific serotonin transporter (SERT) that is present in the presynaptic plasma membrane and is encoded by the 5HTT gene. Many antidepressant drugs are selective serotonin reuptake inhibitors (SSRIs) that inhibit transport of 5-HT by SERT. Perhaps the best-known example of an SSRI is the antidepressant drug Prozac.","{'049c88f5-7e1b-4bcb-9c36-5156c17a5560': 'Serotonin, or 5-hydroxytryptamine (5-HT), was initially thought to increase vascular tone by virtue of its presence in blood serum (hence the name serotonin). 5-HT is synthesized from the amino acid tryptophan, which is an essential dietary requirement. Tryptophan is taken up into neurons by a plasma membrane transporter and hydroxylated in a reaction catalyzed by the enzyme tryptophan-5-hydroxylase (figure 2.9), the rate-limiting step for 5-HT synthesis. Loading of 5-HT into synaptic vesicles is done by the VMAT that is also responsible for loading other monoamines into synaptic vesicles. The synaptic effects of serotonin are terminated by transport back into nerve terminals via a specific serotonin transporter (SERT) that is present in the presynaptic plasma membrane and is encoded by the 5HTT gene. Many antidepressant drugs are selective serotonin reuptake inhibitors (SSRIs) that inhibit transport of 5-HT by SERT. Perhaps the best-known example of an SSRI is the antidepressant drug Prozac.'}"
Figure 1.1,neuroscience/images/Figure 1.1.jpg,"Figure 1.1: Potential fates of glucose oxidation. i. Glucose is oxidized to lactate; ii. Glucose is oxidized through the pentose phosphate pathway (PPP); iii. Glucose is stored as glycogen, which only occurs in astrocytes; iv. Pyruvate can be oxidized through the mitochondria but is not a primary fate. (GLUTs: glucose transporters; MCTs: monocarboxylate transporters; TCA: tricarboxylic acid; DHAP: dihydroxyacetone phosphate; GA3P: glyceraldehyde 3-phosphate)","As a brief review, glucose is taken up by the brain in an insulin-independent manner. The brain oxidizes glucose under most conditions with the exception of starvation states. Once the glucose is phosphorylated to glucose 6-phosphate (by hexokinase), it has three potential fates (figure 1.1):","{'30504ceb-862e-48c1-bc39-4ebd97e7cd2a': 'Ferrier, D. R., ed. Lippincott Illustrated Reviews: Biochemistry, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017,\xa0 Chapter 20: Amino Acid Degradation and Synthesis, Chapter 21: Conversion of Amino Acids to Specialized Products.', 'f814fbb7-0506-470d-be91-332dc7f6e933': 'Lieberman, M., and A. Peet, eds. Marks’ Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 37: Synthesis and Degradation of Amino Acids, Chapter 39: Tetrahydrofolate, Vitamin B12, and S-Adenosylmethionine.', '279012c4-5337-4f17-8e30-15c0a30fd0c7': 'Le, T., and V. Bhushan.\xa0First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 69, 83–85.', '1cb43208-8a51-4579-9c86-2ac4863a85bd': 'Peptide-secreting neurons generally synthesize polypeptides that are much larger than the final, “mature” peptide. Processing these polypeptides, which are called pre-propeptides, takes place within the neuron’s cell body by a sequence of reactions that occur in several intracellular organelles. Pre-propeptides are synthesized in the rough endoplasmic reticulum, where the signal sequence—that is, the sequence of amino acids indicating that the peptide is to be secreted—is removed. The remaining polypeptide,\xa0referred to as the propeptide, moves through the Golgi apparatus and is packaged into vesicles in the trans-Golgi network. The final stages of peptide neurotransmitter processing\xa0involve\xa0proteolytic cleavage and occur\xa0within the Golgi-associated vesicles.\xa0In addition to cleavage,\xa0modification of the ends of the peptide by glycosylation, phosphorylation, and disulfide bond formation is also common.', '43721d34-b597-459d-9a11-fed27bc8628c': 'Purves, D., G. J. Augustine, Dd. Fitzpatrick, L. C. Katz, A.-S. LaMantia, J. O. McNamara, and S. M. Williams, eds. Neuroscience, 2nd ed. Sunderland, MA: Sinauer Associates, 2001, Chapter 6: Neurotransmitters.', '474c3f8f-b2a3-4c5e-bac4-e6ab9d814896': 'Acetylcholine (ACh) was the first identified neurotransmitter and is synthesized in nerve terminals from the precursors acetyl-CoA\xa0and choline, in a reaction catalyzed by choline acetyltransferase (ChAT) (figure 2.1). After synthesis in the cytoplasm of the neuron, a vesicular ACh transporter (VAChT) loads ACh into each cholinergic vesicle. The energy required to concentrate ACh within the vesicle is provided by the acidic pH of the vesicle lumen, which allows the VAChT to exchange H+ for ACh.', '3ef1c28b-edf3-4c7d-8cfe-98104a3884de': '“Biochemistry of Nerve Transmission.” The Medical Biochemistry Page. http://themedicalbiochemistrypage.or…-transmission/.', '5f067d1d-a9fe-42d5-ba5d-00d875139d3a': '“Neurotransmitters and Receptors: Different Classes of Neurotransmitters, and Different Types of Receptors They Bind To.” Khan Academy. https://www.khanacademy.org/science/…heir-receptors.', '54b79b2a-82e4-4d60-8931-2b5fd438204d': 'As a brief review, glucose is taken up by the brain in an insulin-independent manner. The brain oxidizes glucose under most conditions with the exception of starvation states. Once the glucose is phosphorylated to glucose 6-phosphate (by hexokinase), it has three potential fates (figure 1.1):', '0babe716-7b82-4f49-b785-4b7efcc7d5d3': 'What is unique to the brain\xa0is that not all cell types\xa0oxidize glucose to the same extent, but\xa0there is a tight coupling that exists between cell types to support both energy demand and glutamate-mediated neurotransmission. This compartmentalized, coupled metabolism between neurons and astrocytes\xa0is essential for ATP production, neuronal excitability, and adaptations to stress.', '3657c3ea-7aa2-4b93-85f4-ab8eca86a4d2': 'In the context of this chapter, oxidative metabolism refers to the oxidation of a substrate (glucose) through mitochondrial metabolism versus\xa0glycolytic metabolism, which refers to the oxidation of glucose to lactate.', '3582281d-f4e1-4294-88e1-0f77fae600ed': 'To support the high energy demands imposed on neurons, they sustain a high rate of oxidative metabolism for ATP production compared to astrocytes. Despite this high rate of mitochondrial metabolism, glucose uptake is reduced when compared to astrocytes, in part due to the use of lactate as an energy source. Neurons show a preference for lactate over glucose when both substrates are present. There are several reasons why sustaining a low glycolytic rate but high oxidative rate is preferred in this tissue:', '977f700d-dda5-42c2-ab14-a789271e1739': 'To accommodate these two processes, neurons preferentially utilize lactate, which can be readily converted to pyruvate and enter the mitochondria (figure 1.2). The lactate required for neuronal metabolism is produced by astrocytic glucose oxidation and is discussed below.', 'cd766723-9078-4cfe-a5af-7e26de693949': 'Bélanger, M., I. Allaman, and P. J. Magistretti. “Brain Energy Metabolism: Focus on Astrocyte–Neuron Metabolic Cooperation.” Cell Metabolism 14, no. 6 (December 2011): 724–738, https://doi.org/10.1016/j.cmet.2011.08.016.', '7fd59828-b121-4cf5-9bf5-3e7779c2360c': 'Le, T., and V. Bhushan.\xa0First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 87, 314–315.', 'c3528409-5aee-410f-81f0-443b61264194': 'Lieberman, M., and A. Peet, eds. Marks’ Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 46: Metabolism of the Nervous System.', '66a8b8c3-3424-4336-9832-393bb4d42d51': 'Magistretti, P. J., and I. Allaman. “A Cellular Perspective on Brain Energy Metabolism and Functional Imaging.” Neuron 86, no. 4 (May 2015): 883–901, https://doi.org/10.1016/j.neuron.2015.03.035.'}"
Figure 1.2,neuroscience/images/Figure 1.2.jpg,Figure 1.2: Comparison of neuron and astrocyte metabolism. (PDH: pyruvate dehydrogenase complex; PKM1/2: pyruvate kinase isoforms M1 and M2; TCA: tricarboxylic acid; DHAP: dihydroxyacetone phosphate; GA3P: glyceraldehyde 3-phosphate),"To accommodate these two processes, neurons preferentially utilize lactate, which can be readily converted to pyruvate and enter the mitochondria (figure 1.2). The lactate required for neuronal metabolism is produced by astrocytic glucose oxidation and is discussed below.","{'30504ceb-862e-48c1-bc39-4ebd97e7cd2a': 'Ferrier, D. R., ed. Lippincott Illustrated Reviews: Biochemistry, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017,\xa0 Chapter 20: Amino Acid Degradation and Synthesis, Chapter 21: Conversion of Amino Acids to Specialized Products.', 'f814fbb7-0506-470d-be91-332dc7f6e933': 'Lieberman, M., and A. Peet, eds. Marks’ Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 37: Synthesis and Degradation of Amino Acids, Chapter 39: Tetrahydrofolate, Vitamin B12, and S-Adenosylmethionine.', '279012c4-5337-4f17-8e30-15c0a30fd0c7': 'Le, T., and V. Bhushan.\xa0First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 69, 83–85.', '1cb43208-8a51-4579-9c86-2ac4863a85bd': 'Peptide-secreting neurons generally synthesize polypeptides that are much larger than the final, “mature” peptide. Processing these polypeptides, which are called pre-propeptides, takes place within the neuron’s cell body by a sequence of reactions that occur in several intracellular organelles. Pre-propeptides are synthesized in the rough endoplasmic reticulum, where the signal sequence—that is, the sequence of amino acids indicating that the peptide is to be secreted—is removed. The remaining polypeptide,\xa0referred to as the propeptide, moves through the Golgi apparatus and is packaged into vesicles in the trans-Golgi network. The final stages of peptide neurotransmitter processing\xa0involve\xa0proteolytic cleavage and occur\xa0within the Golgi-associated vesicles.\xa0In addition to cleavage,\xa0modification of the ends of the peptide by glycosylation, phosphorylation, and disulfide bond formation is also common.', '43721d34-b597-459d-9a11-fed27bc8628c': 'Purves, D., G. J. Augustine, Dd. Fitzpatrick, L. C. Katz, A.-S. LaMantia, J. O. McNamara, and S. M. Williams, eds. Neuroscience, 2nd ed. Sunderland, MA: Sinauer Associates, 2001, Chapter 6: Neurotransmitters.', '474c3f8f-b2a3-4c5e-bac4-e6ab9d814896': 'Acetylcholine (ACh) was the first identified neurotransmitter and is synthesized in nerve terminals from the precursors acetyl-CoA\xa0and choline, in a reaction catalyzed by choline acetyltransferase (ChAT) (figure 2.1). After synthesis in the cytoplasm of the neuron, a vesicular ACh transporter (VAChT) loads ACh into each cholinergic vesicle. The energy required to concentrate ACh within the vesicle is provided by the acidic pH of the vesicle lumen, which allows the VAChT to exchange H+ for ACh.', '3ef1c28b-edf3-4c7d-8cfe-98104a3884de': '“Biochemistry of Nerve Transmission.” The Medical Biochemistry Page. http://themedicalbiochemistrypage.or…-transmission/.', '5f067d1d-a9fe-42d5-ba5d-00d875139d3a': '“Neurotransmitters and Receptors: Different Classes of Neurotransmitters, and Different Types of Receptors They Bind To.” Khan Academy. https://www.khanacademy.org/science/…heir-receptors.', '54b79b2a-82e4-4d60-8931-2b5fd438204d': 'As a brief review, glucose is taken up by the brain in an insulin-independent manner. The brain oxidizes glucose under most conditions with the exception of starvation states. Once the glucose is phosphorylated to glucose 6-phosphate (by hexokinase), it has three potential fates (figure 1.1):', '0babe716-7b82-4f49-b785-4b7efcc7d5d3': 'What is unique to the brain\xa0is that not all cell types\xa0oxidize glucose to the same extent, but\xa0there is a tight coupling that exists between cell types to support both energy demand and glutamate-mediated neurotransmission. This compartmentalized, coupled metabolism between neurons and astrocytes\xa0is essential for ATP production, neuronal excitability, and adaptations to stress.', '3657c3ea-7aa2-4b93-85f4-ab8eca86a4d2': 'In the context of this chapter, oxidative metabolism refers to the oxidation of a substrate (glucose) through mitochondrial metabolism versus\xa0glycolytic metabolism, which refers to the oxidation of glucose to lactate.', '3582281d-f4e1-4294-88e1-0f77fae600ed': 'To support the high energy demands imposed on neurons, they sustain a high rate of oxidative metabolism for ATP production compared to astrocytes. Despite this high rate of mitochondrial metabolism, glucose uptake is reduced when compared to astrocytes, in part due to the use of lactate as an energy source. Neurons show a preference for lactate over glucose when both substrates are present. There are several reasons why sustaining a low glycolytic rate but high oxidative rate is preferred in this tissue:', '977f700d-dda5-42c2-ab14-a789271e1739': 'To accommodate these two processes, neurons preferentially utilize lactate, which can be readily converted to pyruvate and enter the mitochondria (figure 1.2). The lactate required for neuronal metabolism is produced by astrocytic glucose oxidation and is discussed below.', 'cd766723-9078-4cfe-a5af-7e26de693949': 'Bélanger, M., I. Allaman, and P. J. Magistretti. “Brain Energy Metabolism: Focus on Astrocyte–Neuron Metabolic Cooperation.” Cell Metabolism 14, no. 6 (December 2011): 724–738, https://doi.org/10.1016/j.cmet.2011.08.016.', '7fd59828-b121-4cf5-9bf5-3e7779c2360c': 'Le, T., and V. Bhushan.\xa0First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 87, 314–315.', 'c3528409-5aee-410f-81f0-443b61264194': 'Lieberman, M., and A. Peet, eds. Marks’ Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 46: Metabolism of the Nervous System.', '66a8b8c3-3424-4336-9832-393bb4d42d51': 'Magistretti, P. J., and I. Allaman. “A Cellular Perspective on Brain Energy Metabolism and Functional Imaging.” Neuron 86, no. 4 (May 2015): 883–901, https://doi.org/10.1016/j.neuron.2015.03.035.'}"
Figure 1.3,neuroscience/images/Figure 1.3.jpg,Figure 1.3: Lactate and glutamate shuttling between the astrocyte and the neuron. (GS: glutamine synthetase; GLS: glutaminase; LDH: lactate dehydrogenase; EAATs: excitatory amino acid transporters; MCT: monocarboxylate transporter; GluR: glutamate receptor).,"Astrocytes recycle glutamate through sodium-dependent high-affinity glutamate transporters. Following glutamate uptake, astrocytes also play an important role in transferring this neurotransmitter back to neurons. This transfer is achieved by a process called the glutamate-glutamine cycle, which involves both glutamine synthetase (GS) and glutaminase (GLS) (figure 1.3).","{'15462cd8-bb7b-4a5a-b88e-0cf73680cdfe': 'To terminate synaptic transmission and maintain neuronal excitability, astrocytes play a key role in the rapid removal of neurotransmitters from the synaptic cleft. The removal of glutamate is specifically critical as this is the primary excitatory neurotransmitter, and overstimulation of glutamate receptors is highly toxic to neurons.', '79ed036b-ba19-4089-bbda-6b6be86a03a6': 'Astrocytes recycle glutamate through sodium-dependent high-affinity glutamate transporters. Following glutamate uptake, astrocytes also play an important role in transferring this neurotransmitter back to neurons. This transfer is achieved by a process called the glutamate-glutamine cycle,\xa0which involves both glutamine synthetase (GS) and glutaminase (GLS) (figure 1.3).', 'adec9f56-e2ea-4bc0-8908-d927475ca190': 'Finally, lactate can be used as an energy substrate for neurons for oxidative-derived ATP production (figure 1.3).'}"
Figure 1.3,neuroscience/images/Figure 1.3.jpg,Figure 1.3: Lactate and glutamate shuttling between the astrocyte and the neuron. (GS: glutamine synthetase; GLS: glutaminase; LDH: lactate dehydrogenase; EAATs: excitatory amino acid transporters; MCT: monocarboxylate transporter; GluR: glutamate receptor).,"Astrocytes recycle glutamate through sodium-dependent high-affinity glutamate transporters. Following glutamate uptake, astrocytes also play an important role in transferring this neurotransmitter back to neurons. This transfer is achieved by a process called the glutamate-glutamine cycle, which involves both glutamine synthetase (GS) and glutaminase (GLS) (figure 1.3).","{'15462cd8-bb7b-4a5a-b88e-0cf73680cdfe': 'To terminate synaptic transmission and maintain neuronal excitability, astrocytes play a key role in the rapid removal of neurotransmitters from the synaptic cleft. The removal of glutamate is specifically critical as this is the primary excitatory neurotransmitter, and overstimulation of glutamate receptors is highly toxic to neurons.', '79ed036b-ba19-4089-bbda-6b6be86a03a6': 'Astrocytes recycle glutamate through sodium-dependent high-affinity glutamate transporters. Following glutamate uptake, astrocytes also play an important role in transferring this neurotransmitter back to neurons. This transfer is achieved by a process called the glutamate-glutamine cycle,\xa0which involves both glutamine synthetase (GS) and glutaminase (GLS) (figure 1.3).', 'adec9f56-e2ea-4bc0-8908-d927475ca190': 'Finally, lactate can be used as an energy substrate for neurons for oxidative-derived ATP production (figure 1.3).'}"